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The relationship between glycaemic status and the risk of third, fourth and sixth cranial nerve palsy: a nationwide population-based study (2009–2018)

Eye volume 40, pages 185–191 (2026)Cite this article

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A Correction to this article was published on 19 December 2025

This article has been updated

Abstract

Purpose

The purpose of this study was to evaluate the association between glycaemic status and the incidence of third, fourth, and sixth cranial nerve palsy (CNP).

Methods

This is a retrospective nationwide population-based cohort study using South Korean National Health Insurance Service (NHIS) data since 2009. Health check-up data of 4,067,842 individuals aged from 20 to 90 years in the period from 1 January 2009 to 31 December 2018 were analysed. The subjects were classified according to glycaemic status as follows: non-diabetes, impaired fasting glucose (IFG), newly detected diabetes, diabetes duration <5 years, and diabetes duration ≥5 years. The primary endpoint of this study was the incidence of third, fourth or sixth CNP. Hazard ratio (HR) and 95% confidence interval (CI) of CNP were estimated using Cox proportional hazards regression analysis. In Model 5, we adjusted for age, gender, smoking status, alcohol consumption, physical activity, body mass index, hypertension, dyslipidaemia, and chronic kidney disease.

Results

During the follow-up period (mean, 6.3 years), 5835 cases of third, fourth, or sixth CNP were identified with 4,062,007 control cases. In the adjusted model 5, the adjusted HR for third, fourth, and sixth CNP in the IFG group was 1.098 (95% CI 1.030 - 1.171); in the newly detected diabetes group, 1.779 (95% CI 1.587–1.994); in the diabetes duration <5 years group, 1.921 (95% CI 1.731–2.131); and in the diabetes duration ≥5 years group, 2.571 (95% CI 2.343–2.820). Using the Kaplan-Meier curve, the log-rank test demonstrated an increase in the incidence of CNP proportional to the duration of diabetes (p < 0.001).

Conclusions

This large-scale, population-based cohort study suggests that the risk of third, fourth, and sixth CNP significantly increased in patients with IFG and diabetes compared to those with normal glycaemic status.

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Fig. 1: Flowchart showing the enrolment process of the current study cohort.
Fig. 2: Subgroup analysis of CNP risk according to glycaemic status.
Fig. 3: The cumulative incidence of CNP in diabetic and non-diabetic subjects.

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Change history

  • 09 December 2025

    The original online version of this article was revised: The article “The relationship between glycaemic status and the risk of third, fourth and sixth cranial nerve palsy: a nationwide population-based study (2009–2018)”, written by Chaeyeon Lee, Kyung-Do Han, Juhwan Yoo et al, was originally published open access under a “Creative Commons Attribution (CC BY) license 4.0”. As a result of the author’s/authors' subsequent decision not to publish this article under the open access model, the copyright notice of the article was changed on 19 November 2025 to © The Author(s), under exclusive licence to The Royal College of Ophthalmologists 2025 with all rights reserved.

  • 19 December 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41433-025-04160-y

References

  1. Dosunmu EO, Hatt SR, Leske DA, Hodge DO, Holmes JM. Incidence and etiology of presumed fourth cranial nerve palsy: a population-based study. Am J Ophthalmol. 2018;185:110–4.

    Article  PubMed  Google Scholar 

  2. Fang C, Leavitt JA, Hodge DO, Holmes JM, Mohney BG, Chen JJ. Incidence and etiologies of acquired third nerve palsy using a population-based method. JAMA Ophthalmol. 2017;135:23–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jung EH, Kim SJ, Lee JY, Cho BJ. The incidence and etiology of sixth cranial nerve palsy in Koreans: A 10-year nationwide cohort study. Sci Rep. 2019;9:18419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jung EH, Kim SJ, Lee JY, Cho BJ. The incidence and etiologies of third cranial nerve palsy in Koreans: A 10-year nationwide cohort study. Ophthalmic Epidemiol. 2020;27:460–7.

    Article  PubMed  Google Scholar 

  5. Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations, and evaluation of sixth nerve palsy using a population-based method. Ophthalmology. 2004;111:369–75.

    Article  PubMed  Google Scholar 

  6. Tamhankar MA, Biousse V, Ying GS, Prasad S, Subramanian PS, Lee MS, et al. Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes: a prospective study. Ophthalmology. 2013;120:2264–9.

    Article  PubMed  Google Scholar 

  7. Bendszus M, Beck A, Koltzenburg M, Vince GH, Brechtelsbauer D, Littan T, et al. MRI in isolated sixth nerve palsies. Neuroradiology. 2001;43:742–5.

    Article  CAS  PubMed  Google Scholar 

  8. Akagi T, Miyamoto K, Kashii S, Yoshimura N. Cause and prognosis of neurologically isolated third, fourth, or sixth cranial nerve dysfunction in cases of oculomotor palsy. Jpn J Ophthalmol. 2008;52:32–5.

    Article  PubMed  Google Scholar 

  9. Chou KL, Galetta SL, Liu GT, Volpe NJ, Bennett JL, Asbury AK, et al. Acute ocular motor mononeuropathies: prospective study of the roles of neuroimaging and clinical assessment. J Neurol Sci. 2004;219:35–9.

    Article  PubMed  Google Scholar 

  10. Murchison AP, Gilbert ME, Savino PJ. Neuroimaging and acute ocular motor mononeuropathies: a prospective study. Arch Ophthalmol. 2011;129:301–5.

    Article  PubMed  Google Scholar 

  11. Jacobson DM, McCanna TD, Layde PM. Risk factors for ischemic ocular motor nerve palsies. Arch Ophthalmol. 1994;112:961–6.

    Article  CAS  PubMed  Google Scholar 

  12. Sanders SK, Kawasaki A, Purvin VA. Long-term prognosis in patients with vasculopathic sixth nerve palsy. Am J Ophthalmol. 2002;134:81–4.

    Article  PubMed  Google Scholar 

  13. Watanabe K, Hagura R, Akanuma Y, Takasu T, Kajinuma H, Kuzuya N, et al. Characteristics of cranial nerve palsies in diabetic patients. Diab Res Clin Pr. 1990;10:19–27.

    Article  CAS  Google Scholar 

  14. Greco D, Gambina F, Pisciotta M, Abrignani M, Maggio F. Clinical characteristics and associated comorbidities in diabetic patients with cranial nerve palsies. J Endocrinol Invest. 2012;35:146–9.

    CAS  PubMed  Google Scholar 

  15. Kobashi R, Ohtsuki H, Hasebe S. Clinical studies of ocular motility disturbances: Part 2. Risk factors for ischemic ocular motor nerve palsy [corrected]. Jpn J Ophthalmol. 1997;41:115–9.

    Article  CAS  PubMed  Google Scholar 

  16. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diab Care. 2010;33:2285–93.

    Article  Google Scholar 

  17. El Mansouri Y, Zaghloul K, Amraoui A. Oculomotor paralyses in the course of diabetes-concerning 12 cases. J Fr Ophtalmol. 2000;23:14–8.

    CAS  PubMed  Google Scholar 

  18. Al Kahtani ES, Khandekar R, Al-Rubeaan K, Youssef AM, Ibrahim HM, Al-Sharqawi AH. Assessment of the prevalence and risk factors of ophthalmoplegia among diabetic patients in a large national diabetes registry cohort. BMC Ophthalmol. 2016;16:118.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nanayakkara N, Ranasinha S, Gadowski A, Heritier S, Flack JR, Wischer N, et al. Age, age at diagnosis and diabetes duration are all associated with vascular complications in type 2 diabetes. J Diab Complications. 2018;32:279–90.

    Article  Google Scholar 

  20. Bansal N. Prediabetes diagnosis and treatment: A review. World J Diab. 2015;6:296–303.

    Article  Google Scholar 

  21. World Health Organization, International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia : report of a WHO/IDF consultation Geneva, Switzerland: World Health Organization; 2006.

  22. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diab Care. 2014;37:S81–90.

    Article  Google Scholar 

  23. Seong SC, Kim YY, Park SK, Khang YH, Kim HC, Park JH, et al. Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea. BMJ Open. 2017;7:e016640.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hollander P, Spellman C. Controversies in prediabetes: do we have a diagnosis?. Postgrad Med. 2012;124:109–18.

    Article  PubMed  Google Scholar 

  25. Twigg SM, Kamp MC, Davis TM, Neylon EK, Flack JR, Australian Diabetes Society, et al. Prediabetes: a position statement from the Australian Diabetes Society and Australian Diabetes Educators Association. Med J Aust. 2007;186:461–5.

    Article  PubMed  Google Scholar 

  26. Buysschaert M, Bergman M. Definition of prediabetes. Med Clin North Am. 2011;95:289–97.

    Article  CAS  PubMed  Google Scholar 

  27. Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379:2279–90.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Huang Y, Cai X, Mai W, Li M, Hu Y. Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis. BMJ. 2016;355:i5953.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007;24:137–44.

    Article  PubMed Central  Google Scholar 

  30. Saito T, Watanabe M, Nishida J, Izumi T, Omura M, Takagi T, et al. Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: a randomized controlled trial. Arch Intern Med. 2011;171:1352–60.

    Article  PubMed  Google Scholar 

  31. Mahat RK, Singh N, Arora M, Rathore V. Health risks and interventions in prediabetes: A review. Diab Metab Syndr. 2019;13:2803–11.

    Article  Google Scholar 

  32. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996;39:1377–84.

    Article  CAS  PubMed  Google Scholar 

  33. Schreiber AK, Nones CF, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: Physiopathology and treatment. World J Diab. 2015;6:432–44.

    Article  Google Scholar 

  34. van Dam PS. Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives. Diab Metab Res Rev. 2002;18:176–84.

    Article  Google Scholar 

  35. Dejgaard A. Pathophysiology and treatment of diabetic neuropathy. Diabet Med. 1998;15:97–112.

    Article  CAS  PubMed  Google Scholar 

  36. Greco D, Gambina F, Maggio F. Ophthalmoplegia in diabetes mellitus: a retrospective study. Acta Diabetol. 2009;46:23–6.

    Article  PubMed  Google Scholar 

  37. Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diab Complications. 2008;22:83–7.

    Article  Google Scholar 

  38. Patel SV, Holmes JM, Hodge DO, Burke JP. Diabetes and hypertension in isolated sixth nerve palsy: a population-based study. Ophthalmology. 2005;112:760–3.

    Article  PubMed  Google Scholar 

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Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2021R1A2C1007718).

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Author notes

  1. These authors contributed equally: Chaeyeon Lee, Kyung-Do Han.

Authors and Affiliations

  1. Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Chaeyeon Lee, Kyung-Ah Park & Sei Yeul Oh

  2. Department of Medical Statistics, Catholic University College of Medicine, Seoul, Korea

    Kyung-Do Han

  3. Department of Biomedicine and Health Science, The Catholic University of Korea, Seoul, Republic of Korea

    Juhwan Yoo

Authors
  1. Chaeyeon Lee
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  2. Kyung-Do Han
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Correspondence to Kyung-Ah Park or Sei Yeul Oh.

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The original online version of this article was revised: The article “The relationship between glycaemic status and the risk of third, fourth and sixth cranial nerve palsy: a nationwide population-based study (2009–2018)”, written by Chaeyeon Lee, Kyung-Do Han, Juhwan Yoo et al, was originally published open access under a “Creative Commons Attribution (CC BY) license 4.0”. As a result of the author’s/authors' subsequent decision not to publish this article under the open access model, the copyright notice of the article was changed on 19 November 2025 to © The Author(s), under exclusive licence to The Royal College of Ophthalmologists 2025 with all rights reserved.

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Lee, C., Han, KD., Yoo, J. et al. The relationship between glycaemic status and the risk of third, fourth and sixth cranial nerve palsy: a nationwide population-based study (2009–2018). Eye 40, 185–191 (2026). https://doi.org/10.1038/s41433-025-04011-w

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